Treatment of Vitamin D Deficiency Within a Large Integrated Health Care Delivery System

BACKGROUND: In the past decade, increasing attention has focused on identification and treatment of vitamin D deficiency although repletion  outcomes of pharmacologic vitamin D therapy have not been examined at  a population level. OBJECTIVES: To investigate population trends and outcomes of pharmacologic treatment of vitamin D deficiency. METHODS: We conducted a retrospective cohort study using data from an integrated health system with approximately 3.2 million members. Automated laboratory and pharmacy databases were used to identify patients aged 18 years or older with hypovitaminosis D (defined as a 25-hydroxy-vitamin D [25(OH)D] serum level less than  20 nanograms [ng] per mL) who newly initiated pharmacologic ergocalciferol (50,000 international units [IU] per week) during 2007-2010 and did not have a prescription for ergocalciferol in the prior 12 months. Patients were required to be continuously enrolled for 12 months before and 6 months after ergocalciferol initiation. Age, gender, race/ethnicity, body mass index, and 25(OH)D levels were obtained from health plan electronic medical records and administrative, laboratory, and pharmacy databases. Outcome and predictors of repletion among the subset who received 12 weekly doses of 50,000 IU ergocalciferol (total dose 600,000 IU) were examined using multivariable logistic regression. RESULTS: There were 72,093 vitamin D-deficient patients who newly initiated pharmacologic ergocalciferol. During the study period, the use of ergocalciferol increased nearly 8-fold from 161 per 100,000 adult members in 2007 to 1,241 per 100,000 adult members in 2010. One-fifth (n = 14,727) had severe vitamin D deficiency (25[OH]D level less than  10 ng per mL). Among 23,322 patients receiving 50,000 IU ergocalciferol for 12 weeks in whom subsequent 25(OH)D levels were measured between 90 and 365 days after the index ergocalciferol prescription date, 74.0% achieved 25(OH)D of at least 20 ng per mL, and 35.8% achieved 25(OH)D of at least 30 ng per mL. Increasing age (adjusted odds ratio [OR] 1.02, 95% CI 1.02-1.02) and higher baseline 25(OH)D level (OR 1.11, 95% CI 1.10-1.12) were associated with greater odds of successful repletion. Asian race (OR 0.80, 95% CI 0.73-0.88), Hispanic ethnicity (OR 0.71, 95% CI 0.65-0.77), and increasing overweight/obesity (OR 0.78, 95% CI 0.72-0.85 for body mass index [BMI], 25.0-29.9 kg/m2; OR 0.66, 95% CI 0.60-0.71 for BMI 30.0-39.9 kg/m2; OR 0.53, 95% CI 0.48-0.60 for BMI ≥ 40 kg/m2) were associated with lower odds of repletion compared with BMI 18.5-24.9 kg/m2. CONCLUSIONS: There is increasing recognition and treatment of vitamin D deficiency within the health care setting. Patients of younger age, Asian and Hispanic race/ethnicity, and those who are obese or with more severe vitamin D deficiency may be at greater risk for incomplete repletion using standard regimens and may require additional treatment to achieve optimal levels.

has resulted in greater vitamin D screening efforts and an expanding proportion of physician time spent testing, treating, and educating patients, particularly in the primary care setting. In this study, we analyzed data from a large integrated health care delivery system to assess population trends in ergocalciferol treatment and demographic and clinical factors associated with severity of vitamin D deficiency at baseline. We also evaluated factors associated with repletion adequacy in patients who received 600,000 IU of ergocalciferol administered in 12 weekly doses of 50,000 IU.

■■ Methods Source Population and Identification of the Study Cohort
Kaiser Permanente of Northern California (KPNC) is an integrated health care delivery system caring for more than 3.2 million members annually across northern California. Within the San Francisco and greater Bay Area, approximately one-third of insured adults receive their care through KPNC. The population is racially and ethnically diverse and generally representative of the surrounding regional population except for lower representation of those with extremely low household income. 21 Among health plan members, more than 95% have drug benefits and receive prescriptions from KPNC pharmacies tracked through automated databases. Educational materials pertaining to vitamin D deficiency are available to all KPNC health providers and have increased awareness and screening for vitamin D deficiency in the context of clinical care. However, systematic measurement of vitamin D levels is currently not conducted for the entire adult health plan population.
Using health plan pharmacy records, we identified all adult members aged 18 years or older who newly initiated ergocalciferol (vitamin D2, 50,000 IU) during 2007-2010 and had documented vitamin D deficiency at a threshold of 25(OH)D less than 20 ng per mL within 12 months prior to initiating ergocalciferol. Patients without at least 12 months of continuous health plan enrollment before and at least 6 months after ergocalciferol initiation were excluded. Ergocalciferol is one of the most commonly used forms of prescription vitamin D (in the absence of advanced chronic kidney disease and hypoparathyroidism) 22 and the primary prescription strength vitamin D formulation used within KPNC. We excluded patients with end-stage renal disease defined by receipt of dialysis (using health plan dialysis registry data) or diagnosis of kidney failure (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 584.5-584.9, 585.5, 585.6, and 586) and those receiving calcitriol in the 12 months before the index date (date of the initial ergocalciferol prescription). In addition, because our purpose was to examine the relation of BMI and vitamin D status across a general adult population, we excluded the 2.2% of individuals with missing BMI or values greater than 60 kilograms per squared meter (kg per m 2 ). The study was approved by the Kaiser Foundation Research Institute Institutional Review Board. V itamin D deficiency is a common underdiagnosed condition that has received increasing attention in the United States, particularly in the past decade. [1][2][3] Historically, vitamin D deficiency has been more prevalent in homebound elderly individuals, hospitalized patients, and persons with darker skin color who have a nutritional deficiency or gastrointestinal malabsorptive conditions, 1,2,4-6 but in recent years, several studies also demonstrate that vitamin D status and the efficacy of vitamin D replacement differ depending on body mass index (BMI) and adiposity. [6][7][8] The relationship between vitamin D and body fat remains complex and likely varies by race. 9 While the optimal level of vitamin D (measured as the level of 25-hydroxy-vitamin D [25(OH) D]) continues to be examined, 10 it is known that vitamin D deficiency is highly prevalent in the U.S. adult population. According to the National Health and Nutrition Examination Survey (NHANES), from 2000-2004, 6% of adults aged 20 years or older had a 25(OH)D level at or below 11 nanograms per milliliter (ng per mL), or 27.5 nanomoles per liter (nmol per L). 6 Using a 25(OH)D threshold of 20 ng per mL (50 nmol per L), the proportion with vitamin D deficiency increased to 42%, with the highest rates among blacks (82%) and Hispanics (69%) in the NHANES 2005-2006. 11 Vitamin D levels vary by race, with mean 25(OH)D levels highest among whites, lower among Hispanics, and lowest among blacks of all ages. 6 Common manifestations of vitamin D deficiency include osteomalacia, bone pain, muscle weakness, and gait disorder. 1,12,13 According to the Institute of Medicine (Ross et al. 2011), evidence is strong for achieving optimal levels of 25(OH)D (≥ 20 ng per mL) to support bone health, while the role of vitamin D in prevention of autoimmune disease, cancer, diabetes, and cardiovascular disease is less clear. 14 Supplementation with calcium and vitamin D reduces the risk of clinical fractures with efficacy at a dose range of 700-800 international units (IU) daily. 15 Besides the role of vitamin D in bone health and bone mineral density, 16,17 treatment with vitamin D has been shown to reduce the risk of falls, particularly in patients with pre-existing deficiency. 18,19 However, in one study among elderly community-dwelling women, treatment was associated with an increased risk of falls and fractures; interestingly, this study used a single dose of vitamin D (500,000 IU) once annually, suggesting there may be an optimal range (and/or dosing frequency) of vitamin D supplementation for patients without vitamin D deficiency. 20 As research accumulates on the many possible roles of this prohormone, the need remains to better understand the burden of vitamin D deficiency in various clinical populations and factors relevant to pharmacologic treatment. Furthermore, outcome data with regard to successful vitamin D repletion are limited, particularly the availability of population data examining pharmacologic management of vitamin D deficiency and factors associated with optimal repletion. The increase in physician, patient, and public awareness of vitamin D deficiency

Patient Characteristics and Laboratory Data
Demographic variables, including age at first (index) ergocalciferol prescription, sex, and race/ethnicity were obtained from automated health plan administrative databases. BMI was calculated from height and weight obtained from the electronic medical record, ascertaining the BMI value closest to the index prescription date (more than 80% had BMI measured within 1 year of index prescription). BMI was further classified as underweight (BMI < 18.5 kg per m 2 ), normal (BMI 18.5-24.9 kg per m 2 ), overweight (BMI 25.0-29.9 kg per m 2 ), obese (BMI 30.0-39.9 kg per m 2 ), and severely obese (BMI ≥ 40.0 kg per m 2 ). Levels of 25(OH)D before and after treatment initiation were ascertained using laboratory data from assays conducted using the DiaSorin assay (99% of assays) and assays conducted at Quest Diagnostics (1% of assays). Severe vitamin D deficiency was defined as baseline 25(OH)D level less than 10 ng per mL and moderate vitamin D deficiency as 25(OH)D level between 10-19 ng per mL.
Among the subset of patients who received an initial ergocalciferol prescription for 12 weekly tablets of 50,000 IU (total dose 600,000 IU) and who had 25(OH)D levels measured 90 to 365 days after the index prescription date, we ascertained the proportion of patients achieving 25(OH)D level ≥ 20 ng per mL. The latest 25(OH)D level measured during the 90-to 365-day window and prior to a second ergocalciferol prescription (or refill) was selected to assess treatment outcome. The seasons during which the post-treatment 25(OH)D levels were measured were defined as winter (December through February), spring (March through May), summer (June through August), or fall (September through November).

Statistical Analyses
We calculated the number of vitamin D-deficient patients who newly initiated pharmacologic ergocalciferol per 100,000 adult KPNC members, using the KPNC adult membership as the denominator for each year. Point estimates are documented with 95% confidence intervals. Comparisons between subgroups were conducted using the Pearson chi-square test or Student's t test. Among the subset of patients who received 12 tablets of ergocalciferol and had post-treatment vitamin D levels measured 90 to 365 days after the index prescription, multivariable logistic regression was used to examine independent predictors of repletion to a nondeficient level, defined as 25(OH)D of 20 ng per mL or more. We also tested for a potential interaction between race/ethnicity and BMI category. All analyses were conducted using SAS version 9.1 (SAS Inc., Cary, NC). A 2-sided P value of < 0.05 was considered statistically significant.

■■ Results
As shown in Figure 1, we identified a final cohort of 72,093 adult individuals with 25(OH)D levels less than 20 ng per mL, who received pharmacologic ergocalciferol during the study period and met inclusion and exclusion criteria. The mean (standard deviation [SD]) age was 58.2 (15.9) years, and 76.6% were female. The rate of newly identified patients comprised 161 per 100,000 of the adult KPNC population in 2007 to 1,241 per 100,000 in 2010, increasing nearly 8-fold during the 4-year observation period ( Figure 2). The largest increase occurred in the 31-to 64-year age group, which constituted more than one-half of the total number of newly identified patients each year. As specified by study criteria, all patients had a baseline vitamin D level less than 20 ng per mL, and one-fifth (20.4%) had severe vitamin D deficiency, defined as a level less than 10 ng per mL ( Figure 3). Table 1 shows the demographic and clinical characteristics of the cohort by baseline vitamin D status. A somewhat higher proportion of black patients and those with BMI greater than 40 kg per m 2 were seen among those with severe vitamin D deficiency, defined as 25(OH)D level less than 10 ng per mL, compared with moderate vitamin D deficiency, defined as 25(OH)D level 10-19 ng per mL. Differences in the proportions of newly identified patients with severe versus moderate vitamin D deficiency were also similar across study years, despite the nearly 8-fold increase in the rate of new ergocalciferol initiation identified over time.

Treatment of Vitamin D Deficiency Within a Large Integrated Health Care Delivery System
Overall, 53,773 (74.6%) patients received 12 tablets of 50,000 IU (total dose of 600,000 IU) for the first ergocalciferol prescription; most of these prescriptions (> 94%) had instructions for once-weekly dosing, the standard dosing interval in KPNC for pharmacologic ergocalciferol. Among the 53,773 individuals with an initial prescription for 12 tablets, 23,322 had a subsequent vitamin D level measured 90 to 365 days after the index prescription date. The median number of days from the index prescription date to the latest 25(OH)D level within 365 days was 195 days (interquartile range 124-282 days). Of these 23,322 patients (included in the repletion analysis subcohort), 74.0% achieved a final post-treatment 25(OH) D level of at least 20 ng per mL, and 35.8% achieved a final post-treatment 25(OH)D level of at least 30 ng per mL. Five individuals (0.02%) had a final 25(OH)D level at or exceeding 100 ng per mL with values between 100-115 ng per mL, considered at the upper border of the safety limit. 23 Within this same subset of 23,322 individuals who received 12 weekly tablets of ergocalciferol and had follow-up levels of vitamin D measured 90-365 days after the index prescription, we examined the proportion achieving a post-treatment level of at least 20 ng per mL stratified by baseline 25(OH)D status ( Table 2). For patients with baseline 25(OH)D level of 0-9 ng per mL, 63.6% (2,896 of 4,557 patients) achieved a final posttreatment level of at least 20 ng per mL, significantly lower than the proportion for those with a baseline 25(OH)D level of 10-19 ng per mL (76.6%, 14,369 of 18,765 patients; P < 0.001). For both severe and moderate vitamin D deficient groups, older age, nonobesity, and white race were associated with achieving post-treatment 25(OH)D level ≥ 20 ng per mL.
In multivariable logistic regression that adjusted for age, gender, race, BMI category, year of treatment initiation, pretreatment vitamin D level, season, and time to post-treatment 25(OH)D measurement, increasing age and higher baseline 25(OH)D levels were associated with higher odds of repletion to 25(OH)D levels of at least 20 ng per mL, while Asian race and Hispanic ethnicity were associated with lower odds of repletion compared with white race (Table 3). Furthermore, having a BMI in the overweight, obese, or severely obese range was associated with sequentially lower odds of repletion to 25(OH)D levels of at least 20 ng per mL. No significant interaction was seen between race/ethnicity and BMI category (P = 0.71). The results were also similar for a repletion outcome of 25(OH)D levels of at least 30 ng per mL (data not shown).

■■ Discussion
Within a large integrated health care delivery system of more than 3 million members, we observed a dramatically rising trend in the identification and treatment of vitamin D deficiency, with a nearly 8-fold increase in the number of patients initiating pharmacologic ergocalciferol between 2007 and 2010. These findings may be due to a general increase in provider-initiated screening for vitamin D deficiency, particularly among the middle-aged population where vitamin D testing has not been routinely conducted, in contrast to older populations who may have vitamin D levels measured during evaluation for osteoporosis or post-fracture management. The time period of our study also corresponded with a period of increased attention towards hypovitaminosis D in the medical literature and lay press 1,24 ; the resulting impact on provider and public awareness of vitamin D deficiency might have contributed to increased vitamin D screening and consequent treatment. As most patients had vitamin D levels measured using the same assay, there were no changes in the laboratory assay for 25(OH)D that could have accounted for the dramatic rise in use of pharmacologic ergocalciferol. Whether additional secular trends are driving factors for this dramatic increase in pharmacologic D therapy is an area for further investigation. Among treated patients, the proportions with severe and less severe vitamin D deficiency identified across the 4-year interval were similar, indicating that the increasing numbers were not due to greater treatment of more mild disease. We also found that a larger proportion of patients with severe compared with moderate vitamin D deficiency were of black race and had a BMI of 40 kg per m 2 or greater.
Numerous studies in adults indicate that individuals of African-American ancestry and Hispanic ethnicity have a higher risk of vitamin D deficiency. 6 The variation by race/ ethnicity is likely due to multiple factors, including skin  (18.5-24.9  a fat-soluble vitamin, is much lower in obese individuals compared with nonobese individuals. 23,27 In a study of 60 severely obese women, 62% had levels below the normal range, with much greater mean BMI (51 vs. 42 kg per m 2 ) among those with low vitamin D levels. 28 A large cross-sectional study of 2,026 severely obese Norwegian adults found that about onehalf were vitamin D deficient, with male gender associated with a significantly greater odds of vitamin D deficiency. 29 Data from NHANES also demonstrate a strong association between higher 25(OH)D and lower percent body fat, particularly among patients who are centrally obese. 8 Nutritional deficiencies, compounded by higher intake of calorie-dense foods lacking nutrient value and limited access to unprocessed nutritious foods, may be important contributing factors in select obese and minority populations from disadvantaged neighborhoods. 30 The efficacy of vitamin D replacement is also dependent on BMI, with higher doses required for overweight and obese individuals with hypovitaminosis D. 7 Post-operative bariatric patients represent a growing subgroup that may require extremely large repletion doses due to fat malabsorption. 31 pigmentation, amount of sun exposure based on lifestyle and sunscreen use, nutritional factors, obesity, and dietary and over-the-counter supplement intake of vitamin D. Indeed, Hall et al. (2010) found that vitamin D requirements may be up to 2-fold higher in patients with African ancestry (dark skin pigmentation) and low sun exposure compared with patients who have European ancestry (light skin pigmentation) and high sun exposure. 25 This same study also reported differing levels of sun exposure by ancestry, with those from European heritage having the highest sun exposure, followed in decreasing order by African, North Asian, and Hispanic ethnicity. 25 Race has been found to be an important predictor of vitamin D deficiency independent of BMI and sun exposure. 9,26 We found that the highest prevalence of severe vitamin D deficiency was among patients with severe obesity. While we excluded less than 0.5% of patients with extremely high BMI (> 60 kg per m 2 ), there may be unique pharmacokinetic and lifestyle differences that affect those with a BMI of 40 kg per m 2 or more. One mechanism for the relationship between obesity and vitamin D is the sequestration of vitamin D in adipose tissue. 9,27 It is well known that the bioavailability of vitamin D,

Treatment of Vitamin D Deficiency Within a Large Integrated Health Care Delivery System
Severe Vitamin D Deficiency a n = 4,557 Moderate Vitamin D Deficiency a n =18,765 Post-Treatment < 20 ng per mL n = 1,661

Repletion Outcome for Sample Subgroup Stratified by Baseline Severity of Vitamin D Deficiency
1-year observation window, since early measurements obtained during pharmacologic treatment are more likely to be in the normal range. Our findings suggest that correction of vitamin D deficiency may be more challenging in younger individuals (possibly due to comorbidities that prompted vitamin D screening), in those of Asian and Hispanic race/ethnicity, and in individuals who are obese. Further studies are needed to examine specific clinical subsets within these subgroups with poor repletion outcomes.
Few studies have examined the efficacy of specific pharmacologic regimens of vitamin D. Current guidelines suggest that ergocalciferol 50,000 IU administered weekly for 8 weeks is often effective in correcting vitamin D deficiency in adults, 23,34 with the recognition that obese adults, patients with malabsorption syndromes, and patients on medications affecting vitamin D metabolism will need higher doses. 23 In a small series of 306 patients receiving 36 discrete prescribing regimens, regimens containing a total ergocalciferol dose of more than 600,000 IU achieved vitamin D sufficiency at 25(OH)D levels of at least 30 ng per mL for the majority of cases (64%). 22 The proportion in the present study is somewhat lower, likely due to our focus on the final achieved level of 25(OH)D. A more recent study, conducted with 1,446 patients receiving 29 different ergocalciferol regimens, found that patients prescribed 50,000 to 100,000 IU per week were more likely to achieve 25(OH)D levels of 30 ng per mL or greater when compared with those prescribed less than 50,000 IU. 35 This study also found that obesity was associated with a lower odds of attaining sufficient vitamin D levels. 35 There is currently little published research information pertaining to the interaction of race/ethnic differences, adiposity, and other patient factors on rates of vitamin D repletion following pharmacologic therapy with ergocalciferol. Future studies should examine the specific relationship of these factors, the role of treatment optimization, and the utility of alternative forms of vitamin D in treatmentresistant patients. For instance, vitamin D3 has been shown to be effective in maintaining sufficient levels of circulating 25(OH)D levels, and as little as one-third the equivalent dose may be needed. 1,36,37 Limitations Our study has several limitations. First, we did not examine the efficacy of other ergocalciferol regimens (repletion success was only examined with 12 weekly ergocalciferol tablets), provider prescribing practices, patient adherence, and intake of additional over-the-counter cholecalciferol (D3), and we were able to ascertain post-treatment status based only on measured vitamin D levels obtained in the context of patient care. As such, we cannot exclude the potential influence of demographic and clinical factors on the timing of vitamin D measurement following the first prescription. Second, the treatment outcome at less than 90 days or greater than 365 Pre-operatively, these patients already have a high prevalence of hypovitaminosis D, ranging from at least one-third of whites to more than 70% of black and Hispanic patients reported in the bariatric surgery literature. [31][32][33] Recently published guidelines from the Endocrine Society (Holick et al. 2011) 23 recommend vitamin D treatment to achieve a 25(OH)D level exceeding 30 ng per mL (contrasting with recommendations from the Institute of Medicine, 14 which target a threshold of 20 ng per mL), with higher treatment doses often necessary for patients who are obese or have malabsorption syndromes. One of the goals of the present study was to determine which patients are more likely to demonstrate persistent vitamin D deficiency following pharmacologic repletion therapy. For this reason, we examined the last 25(OH)D level available within the specified   days following the index prescription (or after a second prescription) was not examined in this study. Nonetheless, this is one of the first population-based studies investigating the clinical characteristics and treatment outcomes of patients receiving pharmacologic ergocalciferol. Third, these data were obtained in a northern California population receiving health care and may not be generalizable to the larger U.S. population, where sunlight exposure, the intensity of ultraviolet radiation, and access to health care or coverage may vary.

■■ Conclusions
Among patients with hypovitaminosis D receiving pharmacologic ergocalciferol repletion therapy, 20% had severe vitamin D deficiency. Among the subset who received a total dose of 600,000 IU ergocalciferol in 12 weekly divided doses in whom follow-up vitamin D levels were measured up to 1 year following treatment initiation, age, race/ethnicity, BMI, and severity of vitamin D deficiency were associated with differential rates of repletion to a 25(OH)D level at or above 20 ng per mL. Future studies should examine predictors of repletion failure, parathyroid hormone function and response to repletion, and the role of optimal repletion strategies and/or alternatives for treatment-resistant patients.